Marijuana dependence and withdrawal are increasingly reported, yet adequate treatment options have not been identified. This R01 will expand upon a compelling line of investigation demonstrating that drug discrimination can be used to quantify the behavioral effects of the cannabinoid antagonist SR 141716A in monkeys receiving delta9-THC. Dependence will be established with delta9-THC and withdrawal characterized by directly observable signs, drug discrimination, and neuroendocrine response. Aim 1 will examine a role for cannabinoid and monoamines in the discriminative stimulus effects of delta9-THC withdrawal, induced both by SR 141716A and by temporary discontinuation of A9-THC treatment. Studies will examine a role for cannabinoids and monoamines in the directly observable signs of withdrawal induced by SR 141716A. Collectively, studies in Aim 1 will examine the relative contribution of cannabinoids and monoamines across different indices of withdrawal and will test the hypothesis that monoamines attenuate discriminative measures and not other indices of withdrawal. Aim 2 will examine a role for hypothalamic pituitary adrenal activity (indexed by cortisol and ACTH) in the acute and chronic effects of delta9-THC and will examine a role for CRH antagonists in modifying delta9-THC withdrawal. Drug discrimination will be used in Aim 3 to characterize the subjective effects of inhaled marijuana smoke which represents the predominant route of administration in humans. Studies will examine modification of the discriminative stimulus effects of inhaled marijuana smoke by cannabidiol and cannabinol and blockade of these discriminative stimulus effects by cannabinoid antagonists. A likely future direction will be to characterize dependence that occurs to inhaled marijuana smoke. This application will address a need for understanding the behavioral, pharmacologic, and neuroendocrine determinants of cannabinoid dependence and will examine test compounds for modification of cannabinoid withdrawal and acute marijuana action.